Immunology and Immunotherapy Program
Center for Integrative Biology and Infectious Diseases
OBJECTIVE:
This funding opportunity announcement (FOA) on Immunology of Biofilms evolved from two NIDCR sponsored advisory conferences: Biofilm Network Initiative Meeting (June 2004) and Oral Mucosal Immunology Advisory Meeting (Oct 2004). It aims to stimulate research on host response to microbial biofilms leading to improved strategies for diagnosing, preventing and treating biofilm-associated infectious diseases. Collaborative projects, both domestic and international, that bring together investigators in diverse scientific disciplines studying biofilms are encouraged. An aim of this FOA is to link clinical experts, such as dentists, physicians, and nurses, with basic scientists such as immunologists, microbiologists, material scientists, mathematicians to better identify the clinical problems associated with host response to microbial biofilm associated infection.
BACKGROUND:
A biofilm is an accumulation of microorganisms (bacteria, fungi, and/or protozoa, with associated bacteriophages and other viruses) embedded in a polysaccharide matrix and adherent to solid a biologic or non-biologic surface. Biofilms are clinically important, accounting for over 80 percent of microbial infections in the body. Examples include: infections of the oral soft tissues, teeth and dental implants; middle ear; gastrointestinal tract; urogenital tract; airway/lung tissue; eye; urinary tract prostheses; peritoneal membrane and peritoneal dialysis catheters, in-dwelling catheters for hemodialysis and for chronic administration of chemotherapeutic agents (Hickman catheters); cardiac implants such as pacemakers, prosthetic heart valves, ventricular assist devices, and synthetic vascular grafts and stents; prostheses, internal fixation devices, percutaneous sutures; and tracheal and ventilator tubing. The biofilm-associated microorganisms tend to be far more resistant to antimicrobial agents and make it particularly difficult for the host immune system to render an appropriate response.
Normal mucosal surfaces resist biofilm infections despite continual exposure to commensal and pathogenic bacteria. Rapid killing of deposited organisms probably accounts for some of this resistance. Thus it seems that mucosal surfaces might possess an anti-biofilm defense. Recent symposia and workshops sponsored by the American Society for Microbiology and the NIH have identified understanding the host response to bacterial biofilms as a major gap area in preventing biofilm formation. The need for increased research in the immunology of biofilms is based on numerous factors including:
• The host response to bacterial biofilms treated with antimicrobials has been difficult to understand. Bacteria have evolved and adopted numerous strategies to counteract the action of antimicrobials. Antimicrobial resistance is due to many reasons, e.g. cell wall impermeability, efflux, biofilm formation, and the expression of genes mediating inactivating enzymes. The variety of antimicrobial resistance mechanisms is a major worldwide public health concern as a clinical problem because of the reduced efficacy of antimicrobials.
• The bacteria embedded within clinically-relevant biofilms seem to be resistant to both immunological and non-specific defense mechanisms of the body. The structure of biofilms is such that host immune responses may be directed only at those antigens found on the outer surface of the biofilm, and antibodies and other serum or salivary proteins often fail to penetrate into the biofilm.
• The bacterial biofilm expresses new, and sometimes more virulent, phenotypes. Bacteria found at the bottom of the biofilm look and behave differently as compared to species located at the surface. The host response to such a diverse microflora still remains to be understood.
• Species of bacteria communicate with each other within the biofilm. This process, is called quorum sensing, is responsible for the expression of virulence factors. Also, biofilms increase the opportunity for gene transfer between/among bacteria. Gene transfer can convert a previously avirulent commensal organism to a highly virulent pathogen. The host response to such a dynamic microflora still remains to be understood.
One of the limitations of early approaches used to study infectious organisms in disease is that planktonic (or single cell suspension) bacteria were employed. Although much of what we understand today came from the study of planktonic bacteria, it is now clear that bacteria in the clinical environment live more often as communities of microorganisms (biofilms) than as single cell suspensions. Bacteria within a biofilm differ from their planktonic counterparts in a number of ways. These differences include an inherent resistance to antimicrobial agents and the human immune system. Though much work has been done to address what role the biofilm mode of growth plays in resistance to antimicrobial agents, less work has been published investigating the role of biofilm resistance to the human immune system. Additionally, there have been very few studies addressing the host response to polymicrobial biofilms as are common in periodontal diseases. This FOA will address the gap in current knowledge and will determine the host response to developing polymicrobial biofilms.
The goal of this FOA is to promote 1) a better understanding of host response to biofilms; 2)characterization and effectiveness of the humoral and cellular responses to oral biofilms; 3)evaluation and enhancement of the role of the saliva and innate immune system (for example, complement, defensins, lysozyme) in prevention or elimination of oral biofilms; 4) role and evaluation of antigen presentation mechanisms by dendritic cells, macrophages etc; sex, gender or age related issues involved in the host response to biofilms; 5)evaluation of the genomics and proteomics aspects responsible for enhanced proinflammatory response in the host; and 6) evaluation of polymicrobial induction of cytokines and chemokines in the oral cavity of healthy and patients with periodontal disease.
RESEARCH TOPICS:
Human subject research, as well as the use of appropriate animal models, is acceptable. Examples of research topics are listed below; however the list should not be construed as complete or restrictive. Applicants are encouraged to propose other topics that address the overall goal of this initiative, which is to advance the understanding of the host response to oral biofilms, and the means to control them.
• Studies of host immune responses, both innate and adaptive, to biofilms
• Studies on signaling pathways activated during host-biofilm interaction
• Studies on the role and evaluation of antigen presentation mechanisms involved in the host response to oral biofilms
• Development of improved imaging of immune responses of oral biofilms in situ
• Development of better immunological probes for real-time analysis of oral biofilms
• Development of high throughput methods to identify host immunologic factors that are differentially expressed in oral biofilms
• Development of novel immunological approaches to control pathogenic bacteria by, for example, devising host strategies that favor growth of non-pathogenic microorganisms in biofilm communities
• Development of mathematical models and computer simulations of immune response to oral biofilms
• Sex, gender or age related issues involved in the host response to biofilm, preventition and treatment.
CURRENT PORTFOLIO OVERVIEW:
Currently, NIDCR is not supporting any studies on the host response to biofilms in animals or humans. However, there are related programs involving oral immunology, biophysics and biodynamic and development of oral biofilms. Applicants are encouraged to partner with centers conducting research in such areas like- immunology, microbiology, tissue engineering etc.
FUNDING MECHANISMS:
This initiative will utilize the R01 and R21 mechanisms.